1. Field of the Invention
The present invention relates to the treatment and prevention of acute or chronic pain syndromes.
2. Description of the Related Art/Background Information
Pain sensation is complex and variable. Experiences considered painful by one subject may not be equally painful to another and may vary in the same subject depending on the circumstances presented. In addition, subjective experiences, i.e. xe2x80x9cphantom limb painxe2x80x9d make it clear that there is a strong psychological component to pain. Wingard et al., Human Pharmacology: Molecular to Clinical, Mosby-Year Book, Inc., 1991, p. 383.
Several groups of compounds are used to relieve pain, depending on the severity and duration of the pain sensation, and on the nature of the painful stimulus. Drugs used to relieve mild, moderate or severe pain without causing unconsciousness are generally called analgesics. Mild analgesics that are termed non-narcotic agents include aspirin, acetaminophen and non-steroidal anti-inflammatory drugs. Should non-narcotic based agents prove ineffective, narcotic/opioid analgesic agents such as morphine, codeine, meperidine, and the like are used to treat more severe acute or chronic forms of pain. Ibid., pp. 383, 391-92.
Generally, there are two different types of nociceptive (noxious) stimuli, which are intense enough to be perceived as pain within the human body and can be alleviated by narcotic and non-narcotic analgesic agents. One type, somatic pain, consists of an intense, localized, sharp or stinging sensation. Somatic pain is believed to be mediated by fast-conducting lightly myelinated A-delta fibers that have a high threshold (i.e. require a strong mechanical stimulus to sense pain) and enter into the spinal cord through the dorsal horn of the central nervous system where they terminate mostly in lamina I of the spinal cord. Ibid., p. 383.
The second type of pain, sometimes referred to as visceral pain, is characterized as a diffuse, dull, aching or burning sensation. Visceral pain is believed to be mediated largely by unmyelinated, slower-conducting C-fibers that are polymodal (i.e., mediate mechanical, thermal, or chemical stimuli). C-fibers also enter the spinal cord through the dorsal horn of the central nervous system where they terminate mostly in the outer layer of lamina II of the spinal cord. Ibid., p. 383. Both somatic and visceral pain can be sensed centrally and peripherally within the human body.
Central sensitization, i.e. central pain, takes place within the dorsal horn of the spinal cord, the brain stem, and brain. Amplification of nociceptive input in the spinal cord produces secondary hyperalgesia around the site of injury once central sensitization has begun. Central sensitization is believed to be evoked by A-beta low-threshold mechanoreceptors. Often, central sensitization is initiated by slow synaptic potentials through A-delta and C fibers within the dorsal horn of the central nervous system. The long duration of these slow potentials permit summation of potentials during repetitive nociceptor input and generates progressively greater and longer-lasting depolarization in dorsal horn neurons. Several seconds of C fiber input results in several minutes of postsynaptic depolarization.
This depolarization is believed to result from the activation of N-methyl-D-aspartic acid (NMDA) receptors like glutamate, and activation of the NK-1 tachykinin receptor by substance P and neurokinin A. Activation of these receptors allows an inrush of calcium through ligand and voltage-gated ion channels and activation of guanosine triphosphate (GTP) binding proteins. xe2x80x9cPain and Memoryxe2x80x9d, Pain Clinical Updates, Vol. VII, Iss. 1, Spring 1999, p. 2. These second messengers in turn simulate protein kinase C activity, which enhances the function of ion channels and intracellular enzymes by phosphorylating proteins. Ibid., p. 3.
Another mechanism of central sensitization involves the production of intracellular nitric oxide. It has been proposed that activation of the NMDA receptor leads to an influx of calcium ion, which activates a central enzyme nitric oxide synthetase. Intracellular nitric oxide release stimulates transduction of protein kinase C, increases the effects of glutamate, and may interfere with the release of inhibitory neurotransmitters from inhibitory neurons within the central nervous system, causing increases in pain in both the acute and chronic syndromes. Nitric oxide antagonism is therefore another strategy to prevent central sensitization. Ibid., p. 3.
Peripheral sensitization, i.e. peripheral pain, is generally caused by activating A-delta and C nociceptors. Peripheral sensitization is induced by neurohumoral alterations at the site of injury to the human body and surrounding tissue area. Biochemicals released by tissue injury, such as potassium, prostaglandins, bradykinin, and the like excite nociceptors or increase their sensitivity at the injured site (primary hyperalgesia). Substance P, released by an axon reflex, induces vasodilation and mast cell degranulation, resulting in the release of histamine and serotonin which aid in pro-inflammatory reactions, which in turn sensitize adjacent A-delta and C nociceptors further causing pain stimulation. Increased transduction produces continuous nociceptive input that can induce allodynia, primary hyperalgesia, and secondary hyperalgesia. Ibid., p. 2.
Also within the central nervous system are endogenous pain control systems, which descend the spinal cord through the dorsolateral funiculus to the spinal dorsal horn where they inhibit neurons that are activated by binociceptive stimuli. The higher brain centers connected to these descending systems include the pariaqueductal gray region and various subregions of the medulla within the brain. The neurotransmitters for these systems include substance P, somatostatin, vasoactive intestinal polypeptide, cholecystokinin, calcitonin gene-related peptide, norepinephrine, serotonin and opioid peptides. Ibid., pp. 383-84.
The spinal cord itself also contains opioid receptors, which are mainly localized within laminae-I to III of the dorsal horn within the tract of Lissauer. Of these, the highest density of opioid receptors is generally localized in the inner segment of lamina II. Ibid., p. 384. There are multiple types of opioid receptors within the central nervous system designated as mu, kappa, sigma, and delta receptors, with additional subclasses for each of these receptor types. Activation of these receptors in the brain is believed to be responsible with production of analgesic effects. For example, it is believed that kappa receptors, which exist in the brain""s spinal cord, produce analgesia at the spinal level. The majority of the psychotomimetic effects of opioid drugs, i.e. dysphoria and hallucinations are believed to be mediated by sigma receptors. Delta receptors have a different distribution in the brain, and are thought to be the primary receptor for endogenous opioid pentapeptides, such as enkephalins. Ibid., p. 385.
These types of receptors are located on the membranes of neurons and interaction of agonists, such as narcotic analgesics, with these receptors generally leads to a reduction in excitability and firing rate within the neuron causing a decrease in pain sensation. Agonists of mu receptors, for example, increase the outward flux of potassium ions, which may make the neuron less excitable, causing a decrease in pain. Agonists of kappa receptors more directly inhibit the entry of calcium into a neuron through voltage-dependent calcium channels, again causing a decrease in pain in this manner. Agonists of mu and delta receptors are believed to decrease neuronal cAMP synthesis to decrease pain sensation. Ibid., p. 387.
Thus, the use of opioids, NSAIDS, and many other analgesics within the prior art reduce both central and peripheral sensitization through interaction with the various pain-based receptors within the human body. For example, morphine and most other opioid analgesics elicit an inhibitory neuronal effect within central nervous and gastrointestinal (GI) systems within the human body by interacting with areas of the brain receiving input from the spinal pain-transmitting pathways containing opioid receptors. By suppressing neuronal activity at these receptor points, opioid narcotics produce analgesia and control the pain threshold within a human patient. Yet, opioid narcotics are not without certain negative side effects.
Because opioids cause neuronal depression, frequent side effects which limit the use of such agents in pain treatment settings include drowsiness, lethargy, difficulty in being mobile, respiratory depression, excessive central nervous system depression, weakness in the extremities, and dizziness. Frequently, a patient""s respiratory or central nervous system depression by an opioid analgesic will limit the opioid""s use or cause its discontinuance from that patient""s pain treatment program. This causes prolonged treatment, or use of other agents which may not be as clinically and therapeutically effective.
In addition, patients being treated with opioids also develop tolerance to the agent, requiring higher doses, addition of other opioids to the pain treatment regimen, and the ability to develop physical and psychological addiction to such agents. Further, the prior art has shown that opioids also can exhibit excitatory effects upon opioid receptors. Yet, these excitatory effects manifest themselves as side effects which include restlessness, delirium, mania, and strychnine-like seizure reactions. Such excitatory effects do not occur in all subjects treated with an opioid analgesic, but do appear more prevalently when a patient is treated with morphine or a morphine-like agent. Wingard et al., Human Pharmacology: Molecular to Clinical, Mosby-Year Book, Inc., 1991, p. 390.
Finally, other typical side effects of opioid analgesics include miosis, or constriction of the pupils, nausea, vomiting, prolongation of stomach emptying time, decreased propulsive contractions of the small intestine, and increased tone large intestine to slow transit materials through the GI tract. Ibid., pp. 390-91. As a result, most opioid analgesics are only utilized to treat moderate to severe pain, and are used on a short-term basis, only because of these side effects. Ibid., pp. 391-92.
As an alternative to opioid analgesics, non-narcotic based drugs may be utilized to treat mild to moderate pain, and generally because of their lower central nervous system and respiratory depressive effects, can be given over longer periods of time than opioid analgesics. Such non-narcotic agents include acetylsalicylic acid (aspirin), centrally acting alpha antiadrenergic agents, diflusinal, salsalate, acetaminophen, and nonsteroidal anti-inflammatory agents such as ibuprofen, naproxen, and fenoprofen. Ibid., p. 400.
The mechanism by which acetylsalicylic acid, acetaminophen, diflusinal, salsalate, and nonsteroidal anti-inflammatory agents act to reduce mild to moderate pain is through prostaglandin synthesis inhibition resulting in a decrease in pain receptor stimulation. Prior art studies in humans have shown that certain prostaglandins elicit headaches, pain, and can produce hyperalgesia within the central and peripheral neuronal zones of the human body. Aspirin and related compounds inhibit the enzyme cyclooxygenase and prevent the formation of prostaglandin endoperoxides, PGG and PGH, normally formed from arachidonic acid, to reduce or prevent central and peripheral nerve sensitization and nerve stimulation from internal pain agonists. Ibid., p. 400-401.
However, even prostaglandin synthesis inhibitor agents have shown difficulties within the prior art. Aspirin, for example, has been shown through epidemiological data to be a factor in the occurrence of Reye""s syndrome. In addition, salicylates in general have been shown within the prior art to cause gastrointestinal upset, gastrointestinal hemorrhage, and anti-platelet effects. Ibid., p. 409. Acetominophen, like aspirin, inhibits cyclooxygenase, but has not been associated with Reye""s syndrome or the gastrointestinal effects like that of aspirin. Yet, acetaminophen has been shown within the prior art to cause liver damage, kidney damage, and hematological effects such as hemolytic anemia, neutropenia, and leukopenia. Drug Facts and Comparisons, 1999 ed., 1997, p. 1450.
Lastly, non-steroidal anti-inflammatory drugs, such as ibuprofen, many of which are derived from phenylpropionic acids, can also be used to treat mild to moderate pain, and work mainly by inhibiting cyclooxygenase. These agents exhibit analgesic, anti-inflammatory, and antipyretic effects. These agents, too, however, exhibit numerous negative side effects as well, ranging from gastrointestinal distress, gastrointestinal hemorrhage, and kidney damage. Ibid., p. 409-410.
Centrally acting alpha antiadrenergic agents, such as clonidine, have been shown within the prior art to reduce or prevent central and peripheral nerve agitation. Ibid., p. 967-68, 1444-45. Prior art studies have shown that clonidine, for example, can decrease central and peripheral nerve agitation as well as increased blood pressure through adrenergic impulse inhibition. Yet, centrally acting alpha antiadrenergic agents have been shown to exhibit negative side effects such as central nervous and cardiac system depression, dizziness, drowsiness, lethargy, orthostatic hypotension, and weakness in the extremities. Ibid. In addition, when a centrally acting alpha antiadrenergic agent is added to an already existing pain treatment regimen containing an anxiolytic agent, like lorazepam, an additive effect for dizziness, drowsiness, central and cardiac depression, lethargy, weakness in the extremities, orthostatic hypotension, and difficulty in being mobile occurs. Ibid.
Anxiolytic agents such as benzodiazepines and azaspirodecanediones, although not indicated for the treatment of pain per se, are often employed in pain treatment regimens to decrease the anxiety associated with pain treatment and anxiety associated with further pain stimulus. Yet, the use of anxyiolytic agents in such a pain treatment setting also has the problem of frequent negative side effects.
Clinical neurology literature includes many descriptions of patients having increased drowsiness, dizziness, depression, weakness in the extremities, lethargy, orthostatic hypotension, and difficulty in being mobile associated with treatments utilizing anxiolytic agents and centrally acting alpha antiadrenergic agents for the reduction or prevention of alcohol or narcotic withdrawal symptoms such as anxiety, central and peripheral nerve agitation, and hypertension associated with acute and chronic pain treatment. Dunagan, W. and Ridner, M., Manual of Medical Therapeutics, 26th ed., Boston, Little, Brown, 1989, p. 6-7, 474-75.
Clinical cardiology literature in the prior art includes many descriptions of patients experiencing orthostatic hypotension and other side effects associated with centrally acting alpha antiadrenergic agents utilized to treat hypertension and central and peripheral nerve agitation experienced during alcohol or narcotic withdrawal management. Woodley, M. and Whalen A., Manual of Medical Therapeutics, 27th ed., Boston, Little, Brown, 1992, p. 64-75.
U.S. Pat. No. 5,668,117 to Shapiro, discloses a method of treating neurological diseases and etiology by utilizing carbonyl-trapping agents in combination with previously known medicaments. Shapiro discloses the ability of combining a carbonyl-trapping agent with either a benzodiazepine or a centrally acting alpha antiadrenergic agent.
U.S. Pat. No. 4,829,070 to Boder, discloses the use of a redox carrier system for the site-specific delivery of a centrally acting therapeutic agent to the brain. Boder discloses the ability of attaching a centrally acting alpha antiadrenergic agent or benzodiazepine to the redox carrier system and delivering those agents to the brain.
U.S. Pat. No. 5,855,908 to Stanley, discloses a non-dissolvable dosage form for use in the transdermal delivery of a drug to a patient, which includes clonidine or a benzodiazepine agent, such as lorazepam, as suitable drugs to be carried by the transdermal system.
Despite the sophistication of new analgesic agents and improved understanding of the neurobiological basis of pain, current pain management treatment modalities involving narcotic, non-narcotic, and anxiolytic therapeutic agents have not been able to manage the side effect issues associated with the use of these agents.
In addition, as the dizziness, drowsiness, depression, lethargy, difficulty in being mobile, weakness in the extremities, orthostatic hypotension, respiratory depression, gastrointestinal distress, and renal distress side effects of these agents occur, therapeutic regimens frequently discontinue one agent for a less successful pain control agent. Patients experiencing side effects become mal- or non-compliant in taking the prescribed pain treatment regimen to manage their particular type of pain. Finally, because of the depressive effects of these agents, healthcare personnel treat patient populations of this type more on an in-patient only setting to minimize liability issues and to monitor abuse potentials by such patients taking these particular medications.
Thus, there is a need within the prior art for a pharmaceutical kit, composition, and a method of treatment regimen which reduces or prevents negative side effect outcomes associated with acute or chronic pain treatment modalities without minimization of mild to severe pain control in a variety of patient populations, ranging from the infant to the elderly adult.
A pharmaceutical kit, composition and method of treatment regimen for the management of side effects associated with therapeutic agents used to treat acute and chronic pain syndromes has been discovered, utilizing a centrally acting alpha antiadrenergic agent, central nervous system stimulant agent, and an anxiolytic agent combination. The present invention reduces or prevents the negative side effects of depression, dizziness, drowsiness, lethargy, weakness in the extremities, difficulty in being mobile, orthostatic hypotension, restlessness, delirium and mania associated with therapeutic agents utilized to treat acute and chronic pain syndromes without compromising positive clinical effects of those same therapeutic agents.
By reducing or preventing these side effects, the present invention also decreases the risk of injury to patients and liability to healthcare personnel treating such patient populations. Further, by reducing the risk, such pain treatment patients have an increased opportunity to be treated in an outpatient setting, which in turn decreases the healthcare cost in treating these individuals. Further, by minimizing side effects to patients undergoing pain syndrome treatment with the present invention, incidences of therapeutic agent addiction psychologically or physically are reduced or prevented.
The present invention can be embodied in a variety of pharmaceutically acceptable immediate and sustained release dosage forms and can be delivered to the human body via a variety of medically and pharmaceutically acceptable administration routes.
These and other features, advantages and objects of the present invention will be further understood and appreciated by those skilled in the art by reference to the following specification, claims and appended drawings. A more detailed description of the present invention shall be discussed further below.